HEAT SHOCK PROTEINS AND ULCERATIVE COLITIS: THE START OF A NEW ERA?

We read with great interest the article written by Abou El Azm and coworkers, published in the last issue of the Arab Journal of Gastroenterology [1]. In this article, the authors investigated the molecular expression of heat shock proteins (HSP) 70 and 90 in relation to the grades of inflammation and dysplasia in patients with ulcerative colitis (UC) before and after treatment. In this study, in agreement with other published studies [2–4], the authors not only found a potential role for HSP 70 and HSP 90 for assessment of the activity and prognosis of UC, but also such markers predicted the presence of dysplasia and differentiated it from reactive atypia [1]. HSP had been found not only a marker of active disease, thus considering UC as a ‘‘chaperonopathy by mistake’’, but also show a key role in the psychosocial setting in which inflammatory bowel diseases manifest themselves [5]. Furthermore, they could represent a new diagnostic tool to differentiate the different phenotypes of UC, thus allowing to tailor a targeted approach to better manage UC patients [6]. However, some unresolved issues still remain about the potential roles of HSP in both the acute and the longstanding disease. First, it should be interesting to assess the role of HSP in the infections associated to UC flares, like Clostridium difficile and Cytomegalovirus (CMV) infections. In fact, HSP could be investigated as a further marker of inflammation in case of severe and steroid-refractory disease; with regard to CMV infection, mucosal levels of HSP could differentiate when CMV plays a role of direct pathogen or when it represents merely a ‘‘silent bystander’’. Second, in longstanding UC, an integrated approach of colorectal cancer surveillance, by using the advanced endoscopic imaging together with mucosal markers, like HSP, could result in being markedly helpful, both to clinicians and pathologist. In fact, current guidelines recommend that image-enhanced endoscopy (IEE) may increase the yield of detection of dysplasia, thus representing a reasonable alternative to the random sampling of colon using standard white light [7]. The use of both IEE and new biomarkers, like HSP, predicting future occurrence of colonic neoplasia, could lead to a more centralised approach of UC patients, in which a ‘‘biomarker-based surveillance’’ might play a pivotal rol

NEW THERAPEUTIC PERSPECTIVES IN IRRITABLE BOWEL SYNDROME: TARGETING LOW-GRADE INFLAMMATION, IMMUNO-NEUROENDOCRINE AXIS, MOTILITY, SDECRETION AND BEYOND

Irritable bowel syndrome (IBS) is a chronic, recurring, and remitting functional disorder of the gastrointestinal tract characterized by abdominal pain, distention, and changes in bowel habits. Although there are several drugs for IBS, effective and approved treatments for one or more of the symptoms for various IBS subtypes are needed. Improved understanding of pathophysiological mechanisms such as the role of impaired bile acid metabolism, neurohormonal regulation, immune, dysfunction, the epithelial barrier and the secretory properties of the gut has led to advancements in the treatment of IBS. With regards to therapies for restoring intestinal permeability, multiple studies with prebiotics and probiotics are ongoing, even if to date their efficacy has been limited. In parallel, much progress has been made in targeting low-grade inflammation, especially through the introduction of drugs such as mesalazine and rifaximin, even if a better knowledge of the mechanisms underlying the low-grade inflammation in IBS may allow the design of clinical trials that test the efficacy and safety of such drugs. This literature review aims to summarize the findings related to new and investigational therapeutic agents for IBS, most recently developed in preclinical as well as Phase 1 and Phase 2 clinical studies

INFLAMMATION IN IRRITABLE BOWEL SYNDROME: MYTH OR NEW TREATMENT TARGET?

Low-grade intestinal inflammation plays a key role in the pathophysiology of irritable bowel syndrome (IBS), and this role is likely to be multifactorial. The aim of this review was to summarize the evidence on the spectrum of mucosal inflammation in IBS, highlighting the relationship of this inflammation to the pathophysiology of IBS and its connection to clinical practice. We carried out a bibliographic search in Medline and the Cochrane Library for the period of January 1966 to December 2014, focusing on publications decribing an interaction between inflammation and IBS. Several evidences demonstrate microscopic and molecular abnormalities in IBS patients. Understanding the mechanism underlying low-grade inflammation in IBS may help to design clinical trials to test the efficacy and safety of drugs that target this pathophysiologic mechanism

AMYLOIDOSIS AND INFLAMMATORY BOWEL DISEASE: FACT OR MITH?

Inflammatory Bowel Disease (IBD), which includes both Crohn's Disease (CD) and Ulcerative Colitis (UC), is a chronic idiopathic inflammatory disorder affecting the gastrointestinal tract. Extraintestinal manifestations (EIM) are common in patients with IBD, and occur in 6-47% of patients with CD or UC. EIM can involve organs other than the gastrointestinal tract such as skin, eyes, joints, biliary tract and kidneis. Renal and urinary involvement particularly occurs in 4-23% of patients with IBD. Among the renal complications of IBD, seconfary amyloidosis (AA-type, AAA) is a rare but serious complication. renal amyloidosis has been proven to be the most common lethal manifestation of IBD-associated amyloidosis, since renal involvement rapidly leads to end-stage renal failure. A few studies suggest that AAA is more prevalent in CD than in UC, mainly occurring in male patients with an extensive long-lasting and penetrating ddisease pattern. The therapeutic approaches of IBD-associated AAA are based both on control of the chronic inflammatory process that causes the production and storage of serum amyloid A (SAA), which is a precursor of the amyloid, as well as on destabilizing amyloid fibrils so that they can no longer maintain their pleated sheet configuration; however, in patients with end-stage renal disease, the only therapeutic options still available are hemodyalisis and renal transplantation. Whether effective treatment exists for AAA remain controversial

COULD THE ENDOSCOPIC RESECTION OF A LARGE RECTAL LEIOMYOMA BE AN EFFETCIVE AND SAFE TECHNIQUE?

Summary. Rectal leiomyomas are a rare conditions, with low reported incidence in literature and constitute about 0.1% of rectal tumours; in fact rectal leiomyomas occur in approximately 1 out of 2000-3000 rectal tumors. We report on a patient with a 3 cm semi-pedunculated colonic leiomyoma, which was successfully removed by endoscopic polypectomy after normal saline-epinephrine submucosal injection. When we encounter a tumor during a colonoscopic examination, we usually evaluate the tumor carefully and perform an endoscopic resection when we judge it is appropriate. When a symptomatic smooth muscle tumors smaller than 2 cm are incidentally found on colonoscopy, surgical resection is unnecessary. Furthermore, if a tumor can be lifted with a snare and it is either pedunculated or semi-pedunculated, endoscopic resection might be a safe option. For those tumors with wide-based or exoluminal growth, endoscopic removal should be avoided due to the higher risks of bleeding and perforation. The histological findings of the resected tumor are important. If there is any malignant element that can not be completely eradicated, we would suggest surgical treatment. We believe our process allows to avoid unnecessary surgery and reduces medical costs

POUCHITIS: A TRIDIMENSIONAL VIEW

The preferred surgical treatment of ulcerative colitis (UC) and familial adenomatous polyposis (FAP) is represented by proctocolectomy with ileal pouch-anal anastomosis (IPAA). However, patients with UYC who have undergone IPAA are prone to develop several complications, which include surgery related/mecchanical complications; inflammatory or infectious disoreders; dysplasia or neoplasia; and systemic or metabolic disorders. Pouchitis, which is defined as the acute and/or chronic inflammation of the ileal reservoir, represent the most common long-term adverese sequela after IPAA. Gut microbiota play a pivotal role in the initiation and disease progression of pouchitis. Pouchitis can be classified according to the activity of the disease, the duration of the symptoms, the pattern of the disease or response to antibiotic therapy. Patients with IPAA for UC tend to experience a variety of symptoms that may eventually lead to pouch excision thereby necessitating the construction of a permanent ileostomy. To date, the ethiology, the diagnosis and the medical management of pouchitis represent a clinical challenge. In fact pouchitis range from a disease with an acute antibiotic-responsive presentation to a chronic antibiotic-refractory form, with subsequent different disease mechanism and clinical course. A tridimensional and multidisciplinar approach, including endoscopy, histology, and laboratory testing is widely helpful to identify the diferent phenotypes of the disease and to manage correctly its treatment

EFFICACY OF PNEUMATIC DILATATION FOR THE TREATMENT OF IDIOPATIC ACHALASIA: A SINGLE-CENTRE EXPERIENCE

Pneumatic dilatation (PD) and surgical miotomy (SM) are presentely the best treastments for untreated achalasia, with similar efficacy. There is no information on the relative efficacy of PD in younger compared to older patients. Aim of our study was to compare success rate and safety of PD patients under fifty years old in our Unit with graded PD under fluoroscopic view. Five male and 15 female with a median age of 47 years were treated. Twelve patients were less than fifthy years old (group I) while 8 were older (group II). Median dysphagia questionnaire score was 14 and 13 in group I and II respectively. Technical success was achieved in all patients. Seven patients were previously treated through other techniques. In group I all patients achieved a complete remission of symptoms with significant decrease of the dysphagia questionnaire (3). in group II all patients achieved a complete remissionof symptoms with significant decrease of the dysphagia questionnaire score (4,5) but 3 of them repeated the procedure. In boths groups the efficacy of the dilation was radiologically confirmed. Neither early nor late complications were reported in either groups. In our experience PD was an effective and safe procedure both in young and old patients although the older group had more recurrences, all successfully re-dilated

CLINICAL OUTCOMES OF SELF-EXPAMDABLE METALLIC STENTS IN PALLIATION OF MALIGNANT ANASTOMOTIC STRICTURES: A SINGLE CENTER EXPERIENCE

Background: self-expandable metallic stents (SEMS) are employed as the preferred non surgical palliative treatment for gastric outlet obstruction due to malignancies. Metallic stents are often employed to treat malignant anastomotic obstructions after surgicsl interventions as esophagojejunostomy, gastrojejunostomy and esophagogastrojejunostomy. Methods: this case series reports prospectively the clinical outcomes of SEMS in the palliative care of malignant anastomotic strictures caused by the recurrence gastric cancer follwing gastric surgery as oncological curative treatment, in a series of nine consecutive patients, treated between January 2009 and december 2012 in our center. Results: Nine patients (M:F=8:1) were enrolled in the study. The operation was a total gastrectomy with esophagogastrojejunostomy (n=4), subtotal gastrectomy with Bilroth-II reconstruction (n=4), subtotal gastrectomy with Billroth-II reconstruction (n=3), and subtotal gastrectomy with esophagogastrostomy (n=2). The technical success rate was 88,9%, and the clinical success rate was 88.9%. The reostruction of the stent, due to the ingrowth of the tumor, occurred in 1 patient (11,1%) within 1 month after stent placement. the migration of the stent occurred after the placement of a covered stent in 1 patient who underwent a subtotal gastrectomy (with Billroth-II reconstruction). A case o partial stent dislodgement was treated with the placement of a second stent. The median survival period was 180 days (range, 30-240 days) and the median stent patency was 45 days 8range, 30-90 days). Conclusions: Although the number of the patients treated with SEMS results, in this series, almost small to certainly judge the safety and feasibility of SEMS, we believe that the endoscopic insertion of SEMS seems to be a safe, easily feasible, and effective treatment in the palliative care of malignant anastomotic strictures caused by the recurrence of gastric cancer following gastric surgery. The technical and clinical success, and the onset of complications of this procedure are influenced by several factors, such as the type of anastomosis, the technical features of the stent, and the extent of the underlying tumor

Scanning For Dark Matter Subhalos in Hubble Space Telescope Imaging of 54 Strong Lenses

The cold dark matter (DM) model predicts that every galaxy contains thousands of DM subhalos; almost all other DM models include a physical process that smooths away the subhalos. The subhalos are invisible, but could be detected via strong gravitational lensing, if they lie on the line of sight to a multiply-imaged background source, and perturb its apparent shape. We present a predominantly automated strong lens analysis framework, and scan for DM subhalos in Hubble Space Telescope imaging of 54 strong lenses. We identify two compelling DM subhalo candidates (including one previously found in SLACS0946+1006), where a subhalo is favoured after every systematic test we perform. We find that the detectability of subhalos depends upon the assumed parametric form for the lens galaxy's mass distribution. Comparing fits which assume several more complex mass models reveals $8$ additional (generally lower mass) DM subhalo candidates worthy of further study, and the removal of 7 false positives. We identify 38 non-detections, which are vital to building up enough statistical power to test DM models. Future work will apply even more flexible models to the results of this study, to constrain different DM models. Our full analysis results are available at https://github.com/Jammy2211/autolens_subhalo.Comment: 25 Pages, 15 Figure

Raptor-Mediated Proteasomal Degradation of Deamidated 4E-BP2 Regulates Postnatal Neuronal Translation and NF-κB Activity

The translation initiation repressor 4E-BP2 is deamidated in the brain on asparagines N99/N102 during early postnatal brain development. This post-translational modification enhances 4E-BP2 association with Raptor, a central component of mTORC1 and alters the kinetics of excitatory synaptic transmission. We show that 4E-BP2 deamidation is neuron specific, occurs in the human brain, and changes 4E-BP2 subcellular localization, but not its disordered structure state. We demonstrate that deamidated 4E-BP2 is ubiquitinated more and degrades faster than the unmodified protein. We find that enhanced deamidated 4E-BP2 degradation is dependent on Raptor binding, concomitant with increased association with a Raptor-CUL4B E3 ubiquitin ligase complex. Deamidated 4E-BP2 stability is promoted by inhibiting mTORC1 or glutamate receptors. We further demonstrate that deamidated 4E-BP2 regulates the translation of a distinct pool of mRNAs linked to cerebral development, mitochondria, and NF-κB activity, and thus may be crucial for postnatal brain development in neurodevelopmental disorders, such as ASD